Bismuth subsalicylate suspension



Patented Apr. 29, rear EJNETE.

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BISMUTH SUBSALICYLATE SUSPWSION Walter G. Christiansen, Glen Ridge, N. 3., and John Lewis Deuble, Yeadon, Pa., assignors to E. R. Squibb & Sons, New York, N. Y., a corporation of New York No Drawing. Application September 2, 1938, Serial N0. 228,144

Claims, (01. 167-68) This invention relates to suspensions, especially intramuscularly injectable suspensions, of water-insoluble solids in fatty oils.

Suspensions of relatively water-insoluble solids in fatty oils find useful application in many fields, particularly in medicine; for. example, a suspension of bismuth subsalicylate in a fatty oil is widely used in the treatment of syphilis. Since such apreparation is administered by intramuscular injection, it should be homogeneous (to provide a uniform concentration of medicament),

and relatively fluent (so as to be readily drawn follow injection of such suspensions even when finely-divided bismuth subsalicylate has been used in preparing the suspensions, apparently on account of the clumping of the particles on sedimentation; hence the importance of the physibly because the particles slide over each other.

cians effecting a thorough and uniform resuspensionjust prior to administration, Furthermore, suspensions such as that of bismuth subsalicylate in olive oil could not heretofore be modified by addition of other desirable, but viscosity-increasing, ingredients, because of their already high viscosity.

It is the object of this invention to provide improved suspensions of relatively water insoluble solids in fatty oilsparticularly intramuscularlyiniectable suspensions of relatively water-insoluble solid medicaments in fatty oi1s-in which the rate and extent of settling are reduced, and in which the sediment formed is in such condition that it can readily be resuspended by shaking, to obtain a smooth and uniform suspension. It is an additional object of this invention to provide such suspensions so modified as to permit the incorporation of other desirable, but viscosity-increasing, ingredients.

It has been found that the incorporation of a small proportion of water, and preferably also of a small proportion of an emulsifying agent, into a suspension of a relatively water-insoluble solid in a fatty oil does not materially diminish the fluency of the suspension, results in a substantial reduction of the rate and extent of settling, and modifies the condition of the sediment formed, to permit resuspension with ease and with asurance of a homogeneous product. It

has been'found also that the viscosity of suspen-' sions of relatively water-insoluble solids in fatty oils may be advantageously lowered by replacement of the oil, partially or wholly, with a higher fatty acid ester of a lower aliphatic monohydric alcohol, notably ethyl oleate, thus enabling the addition of desirable, but viscosity-increasing, ingredients.

The mechanism of the improvement obtained by the addition of water and an emulsifying agent is not known with certainty, but apparently is not emulsiflcation, since the formation of an emulsion would adversely aifect the rate of flow of the product, and especially since a substance such as bismuth subsalicylate is practically insoluble in both water and fatty oils. It would seem that the added water is adsorbed by the solid particles in suspension, forming a surface film thereon, and the emulsifying agent dissolves in both the fatty oil phase and the water film .and thus tends to stabilizethe suspension; the

sediment formed by the wet particles is less dense because of the interposed films of water, and is more readily resuspended than otherwise, possimore readily or because of surface-tension or interface tension conditions between the watersurrounded particle and the suspension vehicle. It is not intended, however, that the invention shall be limited by this explanatory hypothesis.

The bismuth subsalicylate may be suspended in any fatty oil (especially of vegetable or animal origin) suitable for intramuscular injection, inter alia, corn oil, cottonseedoil, peanut oil, linseed oil, cod-liver oil, and notably olive oil. Preferably, the fatty oil is pretreated to decolorize it. The proportion of water used in the practice of this invention is small, preferably about 2% by volume of the suspension. The preferred emulsifying agent is calcium oleate; among the other emulsifying agents which may be used in the practice of this invention are lecithin, lanolin, acacia, tragacanth, sodium arabate, karaya gum, glycol mono-oleate, sodium oleate, and diglycol laurate; the amount of emulsifying agent used is preferably less than that which would saturate the fatty-oil vehicle of the suspension.

The suspensions of bismuth subsalicylate in fatty oils may contain other desirable ingredients, such as anesthetic or antiseptic compounds; for example, camphor, creosote, or chloretone. The highviscosity (and consequent difficulty of passage through the needle of the syringe) of chloretone-containing suspensions of bismuth subsalicylate in fatty oils, may be obviated by replacing the oil wholly or partly with a higher fatty acid ester of a lower aliphatic monohydric alcohol, e. g. ethyl oleate, ethyl stearate, methyl laurate, butyl palmitate, or the ethyl esters of A mixture of 7 cc. decolorlzed olive oil, 30 cc. decolorized olive oil saturated with calcium oleate (e. g. by warming the oil in the presence of calcium oleate on a steam bath and filtering) and 6.5 g. of finely-divided bismuth subsalicylate, is milled untilthe mixture is uniform; then, while thoroughly mixing, cc. creosote, 5 g. camphor, and 1 cc. water are added, and the product is made uniform by further milling; the resulting suspension has a clean, white color, and is characterized by the hereinbefore-described advantageous properties.

Olive oil, being usually yellow, would result in a buifor muddy-colored suspension, and is therefore initially decolorized; for example, by agitating with about of its weight of Tonsil at 110 to 120 C. for about five minutes cooling to room temperature, and filtering through a filter aid (e. g. Hyiiocel) on filter paper, to produce an almost water-white product.

Example 2 Example 3 In the manner detailed in Example 1, a suspension of the following composition is prepared:

Finely-divided bismuth subsalicylate kilograms" 5.72

Ethyl oleate liters 35 Calcium oleate grams-- 53 creosote liters 4.4 Camphor "kilograms", 4.4 Distilled water liters 0.88

The suspension has a desirable low viscosity, and is characterized by the advantageous pr perties hereinbefore described.

v Example 4 In the manner detailed in Example 1, a suspension of the following composition is prepared:

Finely-divided bismuth subsalicylate grams" 6.5 Decolorized olive oil cubic centimeters 37 Creosote do 5 Camphor -1 --grams-- 5 Water cubic centimeters-.. 1

This suspension from that of Example 1 only in omission of the emulsifying agent, calcium oleate, but compares favorably with the suspension of Example 1 in rates of flow and of settling.

Example 5 In the manner detailed in Example 1, a suspension of the following composition is prepared:

Finely-divided bismuth subsalicylate grams" 26 Tonsil-treated olive oil cubic centimeters 25.0 Tonsil-treated olive oil saturated with acacia cubic centimeters 120.0 Ethyl oleate do 36.4 Chloretone (anhydrous) grams 6.0 Distilled water cubic centimeters 4.0

The olive oil and acacia mixture is prepared by agitating the olive oil with approximately 0.02% acacia for one hour at C., cooling, and filtering off the excess acacia. The suspension has a satisfactory rate of flow, and is characterized by the advantageous settling and resuspension properties hereinbefore described.

The invention may be variously otherwise embodied, within the scope of the appended claims.

We claim:

l. A normally-liquid suspension essentially comprising finely-divided bismuth subsalicylate, a fatty oil, and a small proportion of water.

2. A normally-liquid suspension essentially comprising finely-divided bismuth subsalicylate, a fatty oil, and small proportions of water and of an emulsifying agent.

3. A normally-liquid suspension essentially comprising finely-divided bismuth subsallcylate, a fatty oil, and about 2% by volume of water.

4. A normally-liquid suspension essentially comprising finely-divided bismuth subsalicylate, a fatty oil, about 2% by volume of water, and an emulsifyin agent in amount less than sumcient to saturate the fatty oil.

5. A normally-liquid suspension essentially comprising finely-divided bismuth subsalicylate, olive oil, about 2% by volume of water, and cal cium oleate in amount less than sufllcient to saturate the olive oil.

6. A normally-liquid suspension essentially comprising finely-divided bismuth subsalicylate. small proportions of water and of an emulsifying agent, and a vehicle of the group consisting of fatty oils, higher fatty acid esters of lower aliphatic monohydric alcohols, and mixtures thereof.

7. A normally-liquid suspension essentially comprising finely-divided bismuth subsalicylate, olive oil, ethyl oleate, and small proportions of water, calcium oleate, and chloretone.

8. A normally-liquid suspension essentially comprising finely-divided bismuth subsalicylate, olive oil, and a small proportion of water.

9. A normally-liquid suspension essentially comprising finely-divided bismuth subsalicylate, ethyl oleate, and small proportions of water and calcium oleate.

10. A normally-liquid suspension essentially comprising finely-divided bismuth subsalicylate, olive oil, about 2% by volume of water and acacia in amount less than suflicient to saturate the olive oil.

-WAL'I'ER G. CHRISTIANSEN.

J. LEWIS DEUBLE. 

